CN1295566A - Trisubstituted 1,3,5-triazine derivatives for treatment by HIV infections - Google Patents

Abstract

This invention concerns the use of the compounds of formula (I) and the pharmaceutically use of treatment of the HIV sufferer of the N-oxides, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein A is CH, CR<4> or N; n is 0, 1, 2, 3 or 4; R<1> and R<2> are each independently selected from hydrogen, hydroxy, C1-12alkyl, C1-12alkyloxy, C1-12alkylcarbonyl, C1-12alkyloxycarbonyl, aryl, amino, mono- or di(C1-12alkyl)amino, mono- or di(C1-12alkyl)aminocarbonyl wherein each of the aforementioned C1-12alkyl groups may optionally and each individually be substituted; or R<1> and R<2> taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C1-12alkyl)aminoC1-4alkylidene; R<3> is hydrogen, aryl, C1-6alkylcarbonyl, optionally substituted C1-6alkyl; and each R<4> independently is hydroxy, halo, C1-6alkyl, C1-6alkyloxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl or trihalomethyloxy; L is -X-R<5> or -X-Alk-R<6>; wherein R<5> and R<6> each independently are indanyl, indolyl or phenyl; each of said indanyl, indolyl or phenyl may be substituted; and X is -NR<3>-, -NH-NH-, -N=N-, -O-, -S-, -S(=O)- or -S(=O)2-; aryl is optionally substituted phenyl; Het is an optionally substituted aliphatic or aromatic heterocyclic radical; for the manufacture of a medicine for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection. It further relates to new compounds being a subgroup of the compounds of formula (I), their preparation and pharmaceutical compositions comprising them.

Description

Trisubstituted 1,3,5-triazine derivatives for the treatment of HIV infection

The present invention relates to trisubstituted 1,3,5-triazine derivatives having HIV replication inhibiting properties. The invention additionally relates to processes for their preparation and pharmaceutical compositions containing them. The invention also relates to the use of said compounds for the manufacture of a medicament for the treatment of patients suffering from HIV (Human Immunodeficiency Virus) infection.

Substituted 1,3,5-triazines are disclosed in the prior art.

For example, ZerkoWski et al. disclosed 4-[4-amino-6-[(4-iodophenyl)amino]-1,3,5 in Chem.Mater.(1994), 6(8),1250-1257 -triazin-2-yl]amino]benzonitrile and it was used to study the crystal structure of the H-bonded complex. US-2,671,810 discloses 4-cyano-anilino-substituted 1,3,5-triazines useful as plasticizers, surfactants and perfume ingredients. Brit. 701,789 discloses the preparation of 4-cyano-anilino-substituted 1,3,5-triazines.

It has now surprisingly been found that compounds of formula (I) are effective in inhibiting the replication of said human immunodeficiency virus (HIV) and are therefore useful in the treatment of HIV-infected individuals.

其中A为CH、CR⁴或N；n为0、1、2、3或4；R¹和R²每一个独立选自氢、羟基、C_1-12烷基、C_1-12烷氧基、C_1-12烷基羰基、C_1-12烷氧基羰基、芳基、氨基、单-或双(C_1-12烷基)氨基、单-或双(C_1-12烷基)氨基羰基，其中前已述及的C_1-12烷基的每一个可任选和单独由一个或两个各独立选自羟基、C_1-6烷氧基、羟基C_1-6烷氧基、羧基、C_1-6烷氧基羰基、氰基、氨基、亚氨基、氨基羰基、氨基羰基氨基、单-或双(C_1-6烷基)氨基、芳基和Het的取代基取代；或者R¹和R²一起可形成吡咯烷基、哌啶基、吗啉基、叠氮基或者单-或双(C_1-12烷基)氨基C_1-4亚烷基；R³为氢、芳基、C_1-6烷基羰基、C_1-6烷基、C_1-6烷氧基羰基、以C_1-6烷氧基羰基取代的C_1-6烷基；和每一个R⁴独立为羟基、卤代、C_1-6烷基、C_1-6烷氧基、氰基、氨基羰基、硝基、氨基、三卤甲基或三卤甲氧基；L为-X-R⁵或-X-Alk-R⁶；其中R⁵和R⁶每一个独立为2，3-二氢化茚基、吲哚基或苯基；所述2，3-二氢化茚基、吲哚基或苯基中的每一个可以一个、两个、三个、四个或五个各独立选自卤代、C_1-6烷基、C_1-6烷氧基、羟基、C_1-6烷基羰基、C_1-6烷氧基羰基、甲酰基、氰基、硝基、氨基和三氟甲基的取代基取代；和X为-NR³-、-NH-NH-、-N=N-、-O-、-S-、-S(=O)-或-S(=O)₂-；Alk为C_1-4链烷二基；芳基为苯基或以一个、两个、三个、四个或五个各独立选自卤代、C_1-6烷基、C_1-6烷氧基、氰基、硝基和三氟甲基的取代基取代的苯基；Het为脂族或芳族杂环基；所述脂族杂环基选自吡咯烷基、哌啶基、高哌啶基、哌嗪基、吗啉基、四氢呋喃基和四氢噻吩基，其中每一个所述脂族杂环基可任选由氧代基团取代；并且所述芳族杂环基选自吡咯基、呋喃基、噻吩基、吡啶基、嘧啶基、吡嗪基和哒嗪基，其中每一个所述芳族杂环基可任选由羟基取代。The present invention relates to the use of compounds of the following formula, their N-oxides, pharmaceutically acceptable addition salts and stereochemical isomers in the preparation of medicines for treating HIV (human immunodeficiency virus) infection :

Wherein A is CH, CR ^or N; n is 0, 1, 2, ³ or 4; R and ^R are each independently selected from hydrogen, hydroxyl, C _1-12 alkyl, C _1-12 alkoxy , C _1-12 alkylcarbonyl, C _1-12 alkoxycarbonyl, aryl, amino, mono- or bis (C _1-12 alkyl) amino, mono- or bis (C _1-12 alkyl) amino Carbonyl, wherein each of the previously mentioned C _1-12 alkyl groups can be optionally and independently selected from one or two independently selected from hydroxyl, C _1-6 alkoxy, hydroxy C _1-6 alkoxy, Substituents of carboxyl, C _1-6 alkoxycarbonyl, cyano, amino, imino, aminocarbonyl, aminocarbonylamino, mono- or bis (C _1-6 alkyl) amino, aryl and Het; or R ¹ and R ² together can form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or bis (C _1-12 alkyl) amino C _1-4 alkylene; R ³ is hydrogen, Aryl, C _1-6 alkylcarbonyl, C _1-6 alkyl, C _1-6 alkoxycarbonyl, C _1-6 alkyl substituted with C _1-6 alkoxycarbonyl; and each R ⁴ independently is hydroxyl, halo, C _1-6 alkyl, C _1-6 alkoxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl or trihalogenmethoxy; L is -XR ⁵ or -X-Alk-R ⁶ ; wherein R ⁵ and R ⁶ are each independently 2,3-indanyl, indolyl or phenyl; said 2,3-indanyl, indolyl or benzene Each of the groups can be one, two, three, four or five independently selected from halo, C _1-6 alkyl, C _1-6 alkoxy, hydroxyl, C _1-6 alkylcarbonyl , C _1-6 alkoxycarbonyl, formyl, cyano, nitro, amino and trifluoromethyl; and X is -NR ³ -, -NH-NH-, -N=N-, -O-, -S-, -S(=O)- or -S(=O) ₂ -; Alk is C _1-4 alkanediyl; aryl is phenyl or one, two, three , four or five phenyls substituted by substituents independently selected from halo, C _1-6 alkyl, C _1-6 alkoxy, cyano, nitro and trifluoromethyl; Het is aliphatic Or aromatic heterocyclic group; The aliphatic heterocyclic group is selected from pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and tetrahydrothiophenyl, wherein each of the The aliphatic heterocyclic group may be optionally substituted by an oxo group; and the aromatic heterocyclic group is selected from pyrrolyl, furyl, thienyl, pyridyl, pyrimidyl, pyrazinyl and pyridazinyl, wherein each One of said aromatic heterocyclic groups may be optionally substituted with hydroxy.

The invention also relates to methods of treating warm-blooded animals suffering from HIV (Human Immunodeficiency Virus) infection. The method comprises administering a therapeutically effective amount of a compound of formula (I) or its N-oxide form, pharmaceutically acceptable addition salt or stereochemical isomeric form in admixture with a pharmaceutically acceptable carrier.

其中所述变量R¹、R²、R³和L如在式(Ⅰ)中定义；和A’为CH或N；R^4’为氰基、氨基羰基、硝基或三氟甲基；条件是当R^4’为氰基，R³为氢，L为其中X为NH和R⁵为4-氰基苯基或4-碘苯基的-X-R⁵时，那么NR¹R²不为NH₂、NH[CH₂CH₂N(C₂H₅)₂]、N(C₂H₅)₂、NHCH₃、NHC₂H₅或NH(4-氰基-苯基)；当R⁴为三氟甲基，R³为氢，L为其中X为NH和R⁵为4-三氟甲基苯基的-X-R⁵时，那么NR¹R²不为NH₂或N[(CH₂)₆CH₃]₂；当R^4’为硝基，R³为氢或甲基，L为其中X为NH或N-CH₃和R⁵为4-氟苯基、2，6-二甲基苯基、4-甲基苯基或4-硝基苯基的-X-R⁵时，那么NR¹R²不为NH芳基、NCH₃芳基、N(芳基)₂、NH₂、NH[CH₂CH₂N(C₂H₅)₂]、NH[CH₂CH₂N(CH₃)₂]、NH[CH₂C(=O)OC₂H₅]、NH[CH₂C(=O)OH]或N(C₂H₅)₂；当R^4’为硝基，R³为氢，L为其中X为S(O)₂或S和R⁵为苯基或4-氯苯基的-X-R⁵时，那么R¹和R²不为以一个或多个羧基取代的芳基或C_1-12烷基；它们的N-氧化物、药学上可接受的加成盐和立体化学异构体形式。Specific embodiments of the present invention relate to compounds of the formula

wherein the variables R ¹ , R ² , R ³ and L are as defined in formula (I); and A' is CH or N; R ^4' is cyano, aminocarbonyl, nitro or trifluoromethyl; proviso is when R ^4' is cyano, R ³ is hydrogen, and L is -XR ⁵ where X is NH and R ⁵ is 4-cyanophenyl or 4-iodophenyl, then NR ¹ R ² is not NH _2. NH[CH ₂ CH ₂ N(C ₂ H ₅ ) ₂ ], N(C ₂ H ₅ ) ₂ , NHCH ₃ , NHC ₂ H ₅ or NH(4-cyano-phenyl); when R ⁴ is Trifluoromethyl ^{, R3} is hydrogen, L is ^-XR5 where X is NH and ^R5 is 4-trifluoromethylphenyl, then ^NR1R2 is not _NH2 or N[( _CH2 ) ₆ CH ₃ ] ₂ ; when R ^4' is nitro, R ³ is hydrogen or methyl, L is where X is NH or N-CH ₃ and R ⁵ is 4-fluorophenyl, 2,6-dimethyl When -XR ⁵ of phenyl, 4-methylphenyl or 4-nitrophenyl, then NR ¹ R ² is not NH aryl, NCH ₃ aryl, N(aryl) ₂ , NH ₂ , NH[ CH ₂ CH ₂ N(C ₂ H ₅ ) ₂ ], NH[CH ₂ CH ₂ N(CH ₃ ) ₂ ], NH[CH ₂ C(=O)OC ₂ H ₅ ], NH[CH ₂ C(= O)OH] or N(C ₂ H ₅ ) ₂ ; when R ^4' is nitro, R ³ is hydrogen, L is where X is S(O) ₂ or S and R ⁵ is phenyl or 4-chlorobenzene When -XR ⁵ of the group, then R ¹ and R ² are not aryl or C _1-12 alkyl substituted with one or more carboxyl groups; their N-oxides, pharmaceutically acceptable addition salts and stereo Chemical isomeric forms.

As in the preceding definitions and as used hereinafter, halo is defined as fluoro, chloro, bromo and iodo; C _1-4 alkyl as a group or part of a group includes those having 1 to 4 carbon atoms Straight-chain and branched saturated hydrocarbon groups, such as methyl, ethyl, propyl, butyl, etc.; C _1-6 alkyl as a group or part of a group includes as defined in C _1-4 alkyl and their higher homologues containing 5 or 6 carbon atoms, such as pentyl or hexyl; C _1-10 alkyl as a group or part of a group includes the same as Straight-chain and branched saturated hydrocarbon radicals as defined in C _1-6 alkyl and their higher homologues containing 7 to 10 carbon atoms, for example heptyl, octyl, nonyl or decyl; as C _1-12 alkyl of a group or part of a group includes straight and branched saturated hydrocarbon groups as defined in C _1-10 alkyl and their higher homologues containing 11 or 12 carbon atoms Substances such as undecyl, dodecyl, etc.; C _1-4 alkylene as a group or part of a group is defined as divalent straight and branched chains having 1 to 4 carbon atoms Hydrocarbons, such as methylene, ethylene, propylene, butylene, etc.; C _1-4 alkanediyl as a group or part of a group includes those defined under C _1-4 alkylene and other divalent straight-chain and branched-chain hydrocarbons having 1 to 4 carbon atoms, such as 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, etc.

When ^R5 is optionally substituted indanyl or indolyl, it is preferably attached to the remainder of the molecule via the fused benzene ring. For example, R ⁵ is a suitable 4-, 5-, 6- or 7-indolyl group.

As used above, the term (=0) forms a carbonyl moiety when attached to a carbon atom.

When any variable (eg, aryl, ^R3 , R4 ^, etc.) occurs more than one time in any constituent, each definition is independent.

A line drawn from a substituent into a ring system indicates that the bond may be attached to any suitable ring atom. For example, ^R4 can be attached to any available carbon atom of the phenyl or pyridyl ring.

Pharmaceutically acceptable addition salts as mentioned above are meant to include the therapeutically active non-toxic acid addition salt forms that the compounds of formula (I) or (I') are able to form. Compounds of formula (I) or (I') having basic properties can be converted into their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid. Suitable acids include, for example, mineral acids such as hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or organic acids such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, Succinic acid (succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, Salicylic acid, p-aminosalicylic acid, pamoic acid and other acids.

The term addition salt also includes said hydrates and said solvent addition forms which the compounds of formula (I) or (I') are able to form. Examples of such forms are eg hydrates, alcoholates and the like.

As used above, the term stereochemically isomeric forms of compounds of formula (I) or (I') are defined as all possible compounds composed of the same atoms that a compound of formula (I) or (I') can have , which are connected by the same sequence of bonds but have different three-dimensional structures that are not interconvertible. Unless otherwise mentioned or indicated, chemical names of compounds include mixtures of all possible stereochemical isomeric forms that said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of formula (I) or (I') in pure form or in admixture with each other are intended to be included within the scope of the present invention.

Some compounds of formula (I) or (I') may also exist in their tautomeric forms. Such forms are intended to be included within the scope of the present invention although not explicitly indicated in the above formulas.

Whenever used hereinafter, the term "compound of formula (I)" or "compound of formula (I')" is meant to also include their N-oxides, pharmaceutically acceptable acid addition salts and all their stereoisomers. Constructive form.

L is suitably -XR ⁵ , wherein R ⁵ is phenyl or one, two, three, four or five are each independently selected from halo, C _1-6 alkyl, C _1-6 alkoxy, A phenyl group substituted by a substituent of cyano group, C _1-6 alkylcarbonyl group, nitro group and trifluoromethyl group.

Also suitable compounds are those compounds of the invention wherein R and ^R are ^2,3 -indanyl or indolyl, each of which is independently selected from 1, 2, 3, 4 or 5 Halo, C _1-6 alkyl, C _1-6 alkoxy, hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, formyl, cyano, nitro, amino and trifluoro The substituent of methyl is optionally substituted; or R ⁵ and R ⁶ are each independently selected from halogenated, C _1-6 alkyl, C _1-6 alkoxy, hydroxyl with 1, 2, 3, 4 or 5 , C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, formyl, cyano, nitro, amino and trifluoromethyl substituent substituted phenyl, whereby at least one of said substituents is relatively -X- or -X-Alk- is in the ortho position;

L is specifically 2,3,4,5,6-pentachloro-phenoxy, 2,3,5,6-tetrafluoro-4-hydroxy-phenoxy, 2,3,6-trichloro-phenoxy Base, 2,4,6-tribromo-3,5-dimethyl-phenoxy, 2,4,6-tribromo-phenoxy, 2,4,6-trichloro-phenoxy, 2 , 4,6-trifluoro-phenoxy, 2,4,6-trimethyl-phenoxy, 2,4-dichloro-3,5,6-trimethyl-phenoxy, 2,4 -Dichloro-6-methyl-phenoxy, 2,4-dichloro-phenoxy, 2,4-dimethyl-phenoxy, 2,5-dimethyl-phenoxy, 2, 6-Dibromo-4-chloro-3,5-dimethyl-phenoxy, 2,6-dibromo-4-methyl-phenoxy, 2,6-dichloro-4-fluoro-phenoxy base, 2,6-dichloro-phenoxy, 2,6-dimethoxy-phenoxy, 2,6-dimethyl-4-nitro-phenoxy, 2,6-dimethyl -phenoxy, 2-acetyl-4,6-dichloro-phenoxy, 2-acetyl-4,6-difluoro-phenoxy, 2-amino-4,6-dichloro-5- Methyl-phenoxy, 4-acetyl-2,6-dimethyl-phenoxy, 4-amino-2,6-dimethyl-phenoxy, 4-bromo-2,6-dimethyl Base-phenoxy, 4-bromo-2-chloro-6-methyl-phenoxy, 4-chloro-2,3,6-trimethyl-phenoxy, 4-chloro-2,6-di Methyl-phenoxy, 4-cyano-2-methoxy-phenoxy, 4-formyl-2,6-dimethyl-phenoxy, 4-iodo-2,6-dimethyl Base-phenoxy, 2,3,4,5,6-pentafluoro-anilino, 2,3,4-trimethoxy-6-(methoxycarbonyl)-anilino, 2,4,6- Tribromo-anilino, 2,4,6-trichloro-anilino, 2,4,6-trimethoxy-anilino, 2,4,6-trimethyl-anilino, 2,4-dichloro -6-methyl-anilino, 2,4-dichloro-6-trifluoromethyl-anilino, 2,6-dibromo-4-isopropyl-anilino, 2,6-dibromo-4 -Methyl-anilino, 2,6-dichloro-4-trifluoromethyl-anilino, 2,6-dichloro-anilino, 2,6-diethyl-anilino, 2,6-di Methyl-anilino, 2-acetyl-5-methyl-anilino, 2-bromo-4,6-difluoro-anilino, 2-chloro-4,6-dimethyl-anilino, 2- Chloro-4-fluoro-5-methyl-anilino, 2-chloro-6-methyl-anilino, 2-ethyl-6-methyl-anilino, 2-isopropyl-6-methyl- Anilino, 3-amino-2,4,6-trimethyl-anilino, 3-bromo-2,4,6-trimethyl-anilino, 3-chloro-2,6-dimethyl-aniline Base, 4-bromo-2,6-diethyl-anilino, 4-bromo-2,6-dimethyl-anilino, 4-bromo-2-chloro-6-methyl-anilino, 4- Methyl-anilino, N-methyl-2,4,6-trimethyl-anilino, 2,4,5-trichloro-phenylthio, 2,4,6-trimethyl-phenylthio , 2,4-dichloro-phenylthio, 2,4-difluoro-phenylthio, 2,4-dimethyl-phenylthio, 2,6-dichloro-phenylthio, 2-chloro- 4-fluoro-phenylthio, 2,4,6-trichloro-phenylhydrazino, 2,6-dichloro-phenylhydrazino, 2,4-dichloro-6-methyl-benzylamino, 2,4-dimethoxy-benzylamino, indol-4-yl-oxyl or 5-acetyl-7-methyl-2,3-indan-4-yl-oxyl;

L is more specifically 2,3,4,5,6-pentachloro-phenoxy, 2,3,6-trichloro-phenoxy, 2,4,6-tribromo-3,5-dimethyl -phenoxy, 2,4,6-tribromo-phenoxy, 2,4,6-trichloro-phenoxy, 2,4,6-trifluoro-phenoxy, 2,4,6- Trimethyl-phenoxy, 2,4-dichloro-3,5,6-trimethyl-phenoxy, 2,4-dichloro-6-methyl-phenoxy, 2,4-chloro -phenoxy, 2,4-methyl-phenoxy, 2,5-dimethyl-phenoxy, 2,6-dibromo-4-chloro-3,5-dimethyl-phenoxy , 2,6-dibromo-4-methyl-phenoxy, 2,6-dichloro-4-fluoro-phenoxy, 2,6-dichloro-phenoxy, 2,6-dimethoxy Base-phenoxy, 2,6-dimethyl-4-nitro-phenoxy, 2,6-dimethyl-phenoxy, 2-acetyl-4,6-difluoro-phenoxy , 4-acetyl-2,6-dimethyl-phenoxy, 4-bromo-2,6-dimethyl-phenoxy, 4-bromo-2-chloro-6-methyl-phenoxy , 4-chloro-2,3,6-trimethyl-phenoxy, 4-chloro-2,6-dimethyl-phenoxy, 4-cyano-2-methoxy-phenoxy, 4-formyl-2,6-dimethyl-phenoxy, 4-iodo-2,6-dimethyl-phenoxy, 2,4,6-tribromo-anilino, 2,4, 6-trichloro-anilino, 2,4,6-trimethoxy-anilino, 2,4,6-trimethyl-anilino, 2,4-dichloro-6-methyl-anilino, 2 , 4-dichloro-6-trifluoromethyl-anilino, 2,6-dibromo-4-isopropyl-anilino, 2,6-dibromo-4-methyl-anilino, 2,6 -Dichloro-4-trifluoromethyl-anilino, 2,6-dichloro-anilino, 2,6-diethyl-anilino, 2,6-dimethyl-anilino, 2-bromo- 4,6-difluoro-anilino, 2-chloro-4,6-dimethyl-anilino, 2-chloro-4-fluoro-5-methyl-anilino, 2-chloro-6-methyl- Anilino, 2-ethyl-6-methyl-anilino, 3-amino-2,4,6-trimethyl-anilino, 3-bromo-2,4,6-trimethyl-anilino, 3-chloro-2,6-dimethyl-anilino, 4-bromo-2,6-diethyl-anilino, 4-bromo-2,6-dimethyl-anilino, 4-bromo-2 -Chloro-6-methyl-anilino, N-methyl-2,4,6-trimethyl-anilino, 2,4,5-trichloro-phenylthio, 2,4,6-trimethyl Base-phenylthio, 2,4-dichloro-phenylthio, 2,4-difluoro-phenylthio, 2,4-dimethyl-phenylthio, 2,6-dichloro-phenylthio , 2-chloro-4-fluoro-phenylthio, 2,4,6-trichloro-phenylhydrazino, 2,6-dichloro-phenylhydrazino, 2,4-dichloro-6-methyl - benzylamino or 5-acetyl-7-methyl-2,3-indan-4-yl-oxyl;

L is preferably 2,3,6-trichloro-phenoxy, 2,4,6-tribromo-3,5-dimethyl-phenoxy, 2,4,6-trichloro-phenoxy, 2,4,6-trifluoro-phenoxy, 2,4,6-trimethyl-phenoxy, 2,4-dichloro-6-methyl-phenoxy, 2,4-dichloro- Phenoxy, 2,4-dimethyl-phenoxy, 2,5-dimethyl-phenoxy, 2,6-dibromo-4-methyl-phenoxy, 2,6-dichloro -4-fluoro-phenoxy, 2,6-dichloro-phenoxy, 2,6-dimethyl-4-nitro-phenoxy, 2,6-dimethyl-phenoxy, 4 -Acetyl-2,6-dimethyl-phenoxy, 4-bromo-2,6-dimethyl-phenoxy, 4-bromo-2-chloro-6-methyl-phenoxy, 4 -Chloro-2,3,6-trimethyl-phenoxy, 4-chloro-2,6-dimethyl-phenoxy, 4-formyl-2,6-dimethyl-phenoxy, 4-iodo-2,6-dimethyl-phenoxy, 2,4,6-tribromo-anilino, 2,4,6-trichloro-anilino, 2,4,6-trimethyl -anilino, 2,4-dichloro-6-methyl-anilino, 2,4-dichloro-6-trifluoromethyl-anilino, 2,6-dibromo-4-isopropyl-aniline 2,6-dibromo-4-methyl-anilino, 2,6-dichloro-4-trifluoromethyl-anilino, 2,6-dichloro-anilino, 2,6-dimethyl Base-anilino, 2-bromo-4,6-difluoro-anilino, 2-chloro-4,6-dimethyl-anilino, 2-chloro-6-methyl-anilino, 2-ethyl -6-methyl-anilino, 3-amino-2,4,6-trimethyl-anilino, 3-bromo-2,4,6-trimethyl-anilino, 3-chloro-2,6 -Dimethyl-anilino, 4-bromo-2,6-dimethyl-anilino, 4-bromo-2-chloro-6-methyl-anilino, N-methyl-2,4,6- Trimethyl-anilino, 2,4,5-trichloro-phenylthio, 2,4,6-trimethyl-phenylthio, 2,4-dichloro-phenylthio, 2,4-di Methyl-phenylthio, 2,6-dichloro-phenylthio, 2-chloro-4-fluoro-phenylthio, 2,4,6-trichloro-phenylhydrazino, 2,6-dichloro - phenylhydrazino, 2,4-dichloro-6-methyl-benzylamino or 5-acetyl-7-methyl-2,3-indan-4-yl-oxy.

Compounds of formula (I) or (I') in which L is -XR ⁵ are of particular interest.

A particular group of compounds are those compounds of formula (I') wherein R ^4' is cyano, L is -XR ⁵ and R ⁵ is not 4-cyanophenyl or 4-iodophenyl, and R ⁵ is specifically Two, three, four or five are independently selected from halo, C _1-6 alkyl, C _1-6 alkoxy, hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy A phenyl group substituted with substituents of carbonyl, formyl, cyano, nitro, amino and trifluoromethyl.

Another special group of compounds are those compounds of formula (I') wherein R ^4' is aminocarbonyl.

Particular compounds are also those compounds of formula (I') wherein A' is CH.

Other particular compounds are also those compounds of formula (I') wherein L is -XR ⁵ , wherein X is -NR ³ -, -NH-NH-, -N=N- or -O- and R ⁵ is 2, 3-indanyl, indolyl or phenyl; each of said 2,3-indanyl, indolyl or phenyl can be independently selected from halogen in two, three, four or five Substitute, C _1-6 alkyl, C _1-6 alkoxy, hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, formyl, cyano, nitro, amino and trifluoromethane The substituent of the group is substituted.

Other particular compounds are those compounds of formula (I') wherein R ^4' is cyano and L is -X-Alk-R ⁶ .

Suitable compounds are those compounds of formula (I') in which R ^4' is aminocarbonyl, trifluoromethyl or cyano and L is 2,3,4,5,6-pentachloro-phenoxy, 2,3 , 5,6-tetrafluoro-4-hydroxy-phenoxy, 2,3,6-trichloro-phenoxy, 2,4,6-tribromo-3,5-dimethyl-phenoxy, 2,4,6-Tribromo-phenoxy, 2,4,6-trichloro-phenoxy, 2,4,6-trifluoro-phenoxy, 2,4,6-trimethyl-benzene Oxygen, 2,4-dichloro-3,5,6-trimethyl-phenoxy, 2,4-dichloro-6-methyl-phenoxy, 2,4-dichloro-phenoxy , 2,4-dimethyl-phenoxy, 2,5-dimethyl-phenoxy, 2,6-dibromo-4-chloro-3,5-dimethyl-phenoxy, 2, 6-Dibromo-4-methyl-phenoxy, 2,6-dichloro-4-fluoro-phenoxy, 2,6-dichloro-phenoxy, 2,6-dimethoxy-benzene Oxygen, 2,6-dimethyl-4-nitro-phenoxy, 2,6-dimethyl-phenoxy, 2-acetyl-4,6-dichloro-phenoxy, 2- Acetyl-4,6-difluoro-phenoxy, 2-amino-4,6-dichloro-5-methyl-phenoxy, 4-acetyl-2,6-dimethyl-phenoxy , 4-amino-2,6-dimethyl-phenoxy, 4-bromo-2,6-dimethyl-phenoxy, 4-bromo-2-chloro-6-methyl-phenoxy, 4-chloro-2,3,6-trimethyl-phenoxy, 4-chloro-2,6-dimethyl-phenoxy, 4-cyano-2-methoxy-phenoxy, 4 -Formyl-2,6-dimethyl-phenoxy, 4-iodo-2,6-dimethyl-phenoxy, 2,3,4,5,6-pentafluoro-anilino, 2 , 3,4-trimethoxy-6-(methoxycarbonyl)-anilino, 2,4,6-tribromo-anilino, 2,4,6-trichloro-anilino, 2,4,6 -Trimethoxy-anilino, 2,4,6-trimethyl-anilino, 2,4-dichloro-6-methyl-anilino, 2,4-dichloro-6-trifluoromethyl- Anilino, 2,6-dibromo-4-isopropyl-anilino, 2,6-dibromo-4-methyl-anilino, 2,6-dichloro-4-trifluoromethyl-anilino , 2,6-dichloro-anilino, 2,6-diethyl-anilino, 2,6-dimethyl-anilino, 2-acetyl-5-methyl-anilino, 2-bromo-anilino 4,6-difluoro-anilino, 2-chloro-4,6-dimethyl-anilino, 2-chloro-4-fluoro-5-methyl-anilino, 2-chloro-6-methyl- Anilino, 2-ethyl-6-methylanilino, 2-isopropyl-6-methyl-anilino, 3-amino-2,4,6-trimethyl-anilino, 3-bromo- 2,4,6-trimethyl-anilino, 3-chloro-2,6-dimethyl-anilino, 4-bromo-2,6-diethyl-anilino, 4-bromo-2,6 -Dimethyl-anilino, 4-bromo-2-chloro-6-methyl-anilino, 4-methyl-anilino, N-methyl-2,4,6-trimethyl-anilino, 2,4,5-Trichloro-phenylthio, 2,4,6-trimethyl-phenylthio, 2,4-dichloro-phenylthio, 2,4-difluoro-phenylthio, 2 , 4-Dimethyl-phenylthio, 2,6-dichloro-phenylthio, 2-chloro-4-fluoro-phenylthio, 2,4,6-trichloro-phenylhydrazino, 2, 6-dichloro-phenylhydrazino, 2,4-dichloro-6-methyl-benzylamino, 2,4-dimethoxy-benzylamino, indol-4-yl-oxyl or 5 -Acetyl-7-methyl-2,3-indan-4-yl-oxyl.

Other suitable compounds are those compounds of formula (I'), wherein R ^4' is nitro and L is 2,3,4,5,6-pentachloro-phenoxy, 2,3,5,6-tetrafluoro -4-Hydroxy-phenoxy, 2,3,6-trichloro-phenoxy, 2,4,6-tribromo-3,5-dimethyl-phenoxy, 2,4,6-tri Bromo-phenoxy, 2,4,6-trichloro-phenoxy, 2,4,6-trifluoro-phenoxy, 2,4,6-trimethyl-phenoxy, 2,4- Dichloro-3,5,6-trimethyl-phenoxy, 2,4-dichloro-6-methyl-phenoxy, 2,4-dichloro-phenoxy, 2,4-dimethyl Base-phenoxy, 2,5-dimethyl-phenoxy, 2,6-dibromo-4-chloro-3,5-dimethyl-phenoxy, 2,6-dibromo-4- Methyl-phenoxy, 2,6-dichloro-4-fluoro-phenoxy, 2,6-dichloro-phenoxy, 2,6-dimethoxy-phenoxy, 2,6- Dimethyl-4-nitro-phenoxy, 2,6-dimethyl-phenoxy, 2-acetyl-4,6-dichloro-phenoxy, 2-acetyl-4,6- Difluoro-phenoxy, 2-amino-4,6-dichloro-5-methyl-phenoxy, 4-acetyl-2,6-dimethyl-phenoxy, 4-amino-2, 6-Dimethyl-phenoxy, 4-bromo-2,6-dimethyl-phenoxy, 4-bromo-2-chloro-6-methyl-phenoxy, 4-chloro-2,3 , 6-trimethyl-phenoxy, 4-chloro-2,6-dimethyl-phenoxy, 4-cyano-2-methoxy-phenoxy, 4-formyl-2,6 -Dimethyl-phenoxy, 4-iodo-2,6-dimethyl-phenoxy, 2,3,4,5,6-pentafluoro-anilino, 2,3,4-trimethoxy Base-6-(methoxycarbonyl)-anilino, 2,4,6-tribromo-anilino, 2,4,6-trichloro-anilino, 2,4,6-trimethoxy-anilino , 2,4,6-trimethyl-anilino, 2,4-dichloro-6-methyl-anilino, 2,4-dichloro-6-trifluoromethyl-anilino, 2,6- Dibromo-4-isopropyl-anilino, 2,6-dibromo-4-methyl-anilino, 2,6-dichloro-4-trifluoromethyl-anilino, 2,6-dichloro -anilino, 2,6-diethyl-anilino, 2-acetyl-5-methyl-anilino, 2-bromo-4,6-difluoro-anilino, 2-chloro-4,6- Dimethyl-anilino, 2-chloro-4-fluoro-5-methyl-anilino, 2-chloro-6-methyl-anilino, 2-ethyl-6-methyl-anilino, 2- Isopropyl-6-methyl-anilino, 3-amino-2,4,6-trimethyl-anilino, 3-bromo-2,4,6-trimethyl-anilino, 3-chloro- 2,6-Dimethyl-anilino, 4-bromo-2,6-diethyl-anilino, 4-bromo-2,6-dimethyl-anilino, 4-bromo-2-chloro-6 -Methyl-anilino, 4-methyl-anilino, N-methyl-2,4,6-trimethyl-anilino, 2,4,5-trichloro-phenylthio, 2,4, 6-Trimethyl-phenylthio, 2,4-dichloro-phenylthio, 2,4-difluoro-phenylthio, 2,4-dimethyl-phenylthio, 2,6-dichloro -Phenylthio, 2-chloro-4-fluoro-phenylthio, 2,4,6-trichloro-phenylhydrazino, 2,6-dichloro-phenylhydrazino, 2,4-dichloro- 6-methyl-benzylamino, 2,4-dimethoxy-benzylamino, indol-4-yl-oxyl or 5-acetyl-7-methyl-2,3-indane- 4-yl-oxyl.

Important groups of compounds are compounds of formula (I) or (I') of those groups in which one or more of the following conditions are met:

i. ^R and R ^are each independently selected from hydrogen, aryl or hydroxy; R ^is especially hydrogen and ^R is especially hydrogen or hydroxy;

ii. R ³ is hydrogen or C _1-6 alkyl;

ⅲ.L comprises phenyl or phenyl substituted with one, two, three, four or five substituents, suitably two, three, four or five substituents, each substituent independently selected From halogenated, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxycarbonyl, cyano, amino, trifluoromethyl, nitro, C _1-6 alkylcarbonyl and formyl; and more particularly these substituents are selected from fluorine, bromine, chlorine, cyano, methyl, ethyl, isopropyl and acetyl;

ⅳ. R ⁵ or R ⁶ is indolyl, 2,3-indanyl, phenyl, substituted with two or three independently selected from C _1-6 alkyl and C _1-6 alkylcarbonyl Indanyl substituted with radical, or phenyl substituted with one, two, three, four or five substituents, suitably two, three, four or five substituents , each substituent is independently selected from halo, hydroxyl, C _1-4 alkyl, methoxy, methoxycarbonyl, cyano, amino, trifluoromethyl, nitro, methylcarbonyl and formyl;

v. X is -O-, -S-, -NR ³ , -NH-NH- or -N=N-; especially -O- or -NH-;

ⅵ. Alk is methylene.

Other compounds of interest are those compounds of formula (I) in which n is 1, A is CH and R is cyano or aminocarbonyl, R being more particularly cyano substituted at ^{the 4} position relative to the NR ^moiety .

Other still important compounds are those compounds of formula (I) in which ^R4 is halogen substituted at the 4-position relative to the ^NR3 moiety, ^R1 and ^R2 are each independently selected from hydrogen, hydroxyl, _{C1- 12} alkyl, C _1-12 alkoxyl, C _1-12 alkylcarbonyl, C _1-12 alkoxycarbonyl, amino, mono- or bis (C _1-12 alkyl) amino, mono- or bis ( C _1-12 alkyl) aminocarbonyl, wherein each of the previously mentioned C _1-12 alkyl can be optionally and independently selected from one or two independently selected from hydroxyl, C _1-6 alkoxy, hydroxyl C _1-6 alkoxy, carboxyl, C _1-6 alkoxycarbonyl, cyano, amino, imino, aminocarbonyl, aminocarbonylamino, mono- or bis (C _1-6 alkyl) amino, aryl Substituting with a substituent of Het; or R ¹ and R ² together can form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or bis (C _1-12 alkyl) amino C _1-4 ylidene Alkyl; and L is 2,3,4,5,6-pentachloro-phenoxy, 2,3,5,6-tetrafluoro-4-hydroxy-phenoxy, 2,3,6-trichloro -phenoxy, 2,4,6-tribromo-3,5-dimethyl-phenoxy, 2,4,6-tribromo-phenoxy, 2,4,6-trichloro-phenoxy Base, 2,4,6-trifluoro-phenoxy, 2,4,6-trimethyl-phenoxy, 2,4-dichloro-3,5,6-trimethyl-phenoxy, 2,4-Dichloro-6-methyl-phenoxy, 2,4-dichloro-phenoxy, 2,4-dimethyl-phenoxy, 2,5-dimethyl-phenoxy , 2,6-dibromo-4-chloro-3,5-dimethyl-phenoxy, 2,6-dibromo-4-methyl-phenoxy, 2,6-dichloro-4-fluoro -phenoxy, 2,6-dichloro-phenoxy, 2,6-dimethoxy-phenoxy, 2,6-dimethyl-4-nitro-phenoxy, 2,6- Dimethyl-phenoxy, 2-acetyl-4,6-dichloro-phenoxy, 2-acetyl-4,6-difluoro-phenoxy, 2-amino-4,6-dichloro -5-methyl-phenoxy, 4-acetyl-2,6-dimethyl-phenoxy, 4-amino-2,6-dimethyl-phenoxy, 4-bromo-2,6 -Dimethyl-phenoxy, 4-bromo-2-chloro-6-methyl-phenoxy, 4-chloro-2,3,6-trimethyl-phenoxy, 4-chloro-2, 6-Dimethyl-phenoxy, 4-cyano-2-methoxy-phenoxy, 4-formyl-2,6-dimethyl-phenoxy, 4-iodo-2,6 -Dimethyl-phenoxy, 2,3,4,5,6-pentafluoro-anilino, 2,3,4-trimethoxy-6-(methoxycarbonyl)-anilino, 2,4 , 6-tribromo-anilino, 2,4,6-trichloro-anilino, 2,4,6-trimethoxy-anilino, 2,4,6-trimethyl-anilino, 2,4 -Dichloro-6-methyl-anilino, 2,4-dichloro-6-trifluoromethyl-anilino, 2,6-dibromo-4-isopropyl-anilino, 2,6-di Bromo-4-methyl-anilino, 2,6-dichloro-4-trifluoromethyl-anilino, 2,6-dichloro-anilino, 2,6-diethyl-anilino, 2- Acetyl-5-methyl-anilino, 2-bromo-4,6-difluoro-anilino, 2-chloro-4,6-dimethyl-anilino, 2-chloro-4-fluoro-5- Methyl-anilino, 2-chloro-6-methyl-anilino, 2-ethyl-6-methyl-anilino, 2-isopropyl-6-methyl-anilino, 3-amino-2 , 4,6-trimethyl-anilino, 3-bromo-2,4,6-trimethyl-anilino, 3-chloro-2,6-dimethyl-anilino, 4-bromo-2, 6-diethyl-anilino, 4-bromo-2,6-dimethyl-anilino, 4-bromo-2-chloro-6-methyl-anilino, 4-methyl-anilino, N- Methyl-2,4,6-trimethyl-anilino, 2,4,5-trichloro-phenylthio, 2,4,6-trimethyl-phenylthio, 2,4-dichloro- Phenylthio, 2,4-difluoro-phenylthio, 2,4-dimethyl-phenylthio, 2,6-dichloro-phenylthio, 2-chloro-4-fluoro-phenylthio, 2,4,6-Trichloro-phenylhydrazino, 2,6-dichloro-phenylhydrazino, 2,4-dichloro-6-methyl-benzylamino, 2,4-dimethoxy - benzylamino, indol-4-yl-oxy or 5-acetyl-7-methylindan-4-yl-oxy.

Particular compounds are those compounds of formula (I) or (I') wherein ^R1 is hydrogen, ^R2 is hydrogen, aryl or hydroxy, ^R3 is hydrogen and X is -O- or -NH-.

Other specific compounds are those compounds of formula (I) or (I'), wherein R ⁵ or R ⁶ are 2,4-disubstituted-, 2,5-disubstituted-, 2,6-disubstituted- , 2,3,6-trisubstituted-, 2,4,6-trisubstituted-, 2,3,4,6-tetrasubstituted-, 2,4,5,6-tetrasubstituted- or 2 , 3,4,5,6-pentasubstituted phenyl; especially 2,3,4,5,6-pentahalogen, 2,3,5,6-tetrahalogen-4-hydroxyl-, 2,3, 6-trihalogen-, 2,4,5-trihalogen-, 2,4,6-trihalogen-3,5-diC _1-4 alkyl-, 2,4,6-tri-C _1-4 alkane Base-, 2,4,6-three C _1-4 alkoxy-, 2,4-dihalo-3,5,6-three C _1-4 alkyl-, 2,4-dihalo-6- C _1-4 alkyl-, 2,4-dihalo-6-trifluoromethyl-, 2,4-dihalo-, 2,4-two C _1-4 alkyl-, 2,5-diC _1-4- alkyl-, 2,6-dihalo-4-C _1-4- alkyl-, 2,6-dihalo-4-C _1-4- alkyl-, 2,6-dihalo-4- Trifluoromethyl-, 2,6-dihalo-, 2,6-diC _1-4 alkoxy-, 2,6-diC _1-4 alkyl-4-nitro-, 2,6- Two C _1-4 alkyl-, 2-acetyl-4,6-dihalo-, 2-acetyl-4,6-dihalo-, 2-acetyl-5-C _1-4 alkyl-, 2-amino-4,6-dihalo-5-C _1-4 alkyl-, 2-halo-4,6-di-C _1-4 alkyl-, 2,4-dihalo-5-C _{1- 4-} alkyl-, 2-halo-6-C _1-4 alkyl-, 2,6-two C _1-4 alkyl-, 3-amino-2,4,6-tri-C _1-4 alkyl- , 3-halo-2,4,6-tri-C _1-4 alkyl-, 3-halo-2,6-di-C _1-4- alkyl-, 4-acetyl-2,6-di-C _{1- 4-} Alkyl, 4-amino-2,6-diC _1-4 alkyl-, 4-halo-2,6-diC _1-4 alkyl-, 4-halo-2,3,6-tri-C _1-4 alkyl-, 4-cyano-2-C _1-4 alkoxy-, 4-formyl-2,6-two C _1-4 alkyl-, 4-C _1-4 alkyl- or 2,3,4-tri-C _1-4 alkoxy-6-(C _1-4 alkoxycarbonyl)-phenyl; R ⁵ or R ⁶ is more particularly 2,3,4,5,6- Pentachloro-, 2,3,4,5,6-pentafluoro-, 2,3,5,6-tetrafluoro-4-hydroxy-, 2,3,6-trichloro-, 2,4,5- Trichloro-, 2,4,6-tribromo-3,5-dimethyl-, 2,4,6-tribromo-, 2,4,6-trichloro-, 2,4,6-trifluoro -, 2,4,6-trimethyl-, 2,4,6-trimethoxy-, 2,4-dichloro-3,5,6-trimethyl-, 2,4-dichloro-6 -Methyl-, 2,4-dichloro-6-trifluoromethyl, 2,4-dichloro-, 2,4-difluoro-, 2,4-dimethyl-, 2,5-dimethyl Base-, 2,6-dibromo-4-chloro-3,5-dimethyl-, 2,6-dibromo-4-isopropyl-, 2,6-dibromo-4-methyl-, 2,6-dichloro-4-trifluoromethyl-, 2,6-dichloro-4-fluoro-, 2,6-dichloro-, 2,6-dimethoxy-, 2,6-di Methyl-4-nitro-, 2,6-dimethyl-, 2,6-diethyl-, 2-acetyl-4,6-dichloro-, 2-acetyl-4,6-di Fluoro-, 2-acetyl-5-methyl-, 2-amino-4,6-dichloro-5-methyl-, 2-bromo-4,6-difluoro-, 2-chloro-4,6 -Dimethyl-, 2-chloro-4-fluoro-5-methyl-, 2-chloro-4-fluoro-, 2-chloro-6-methyl-, 2-ethyl-6-methyl-, 2-isopropyl-6-methyl-, 3-amino-2,4,6-trimethyl-, 3-bromo-2,4,6-trimethyl-, 3-chloro-2,6- Dimethyl-, 4-acetyl-2,6-dimethyl-, 4-amino-2,6-dimethyl-, 4-bromo-2,6-diethyl-, 4-bromo-2 , 6-dimethyl-, 4-bromo-2-chloro-6-methyl-, 4-chloro-2,3,6-trimethyl-, 4-chloro-2,6-dimethyl-, 4-cyano-2-methoxy-, 4-formyl-2,6-dimethyl-, 4-iodo-2,6-dimethyl-, 4-methyl- or 2,3, 4-trimethoxy-6-(methoxycarbonyl)-phenyl.

Preferred compounds are those of formula (I'), wherein A' is CH, R ^4' is cyano, X is -O- or -NH- and R ⁵ or R ⁶ are two or three independent A phenyl group substituted with a substituent selected from halo, C _1-6 alkyl, C _1-6 alkylcarbonyl, formyl, nitro or cyano.

The most preferred compound is 4-[[4-amino-6-(2,6-dimethylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[ 4-amino-6-[(2-chloro-6-methylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-amino-6- [(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-(hydroxylamino)-6-[( 2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-amino-6-[(2-ethyl- 6-methylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-amino-6-[(2,6-dichlorophenyl)sulfur Generation]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-(hydroxylamino)-6-[(2,4,6-trichlorophenyl)amino]- 1,3,5-Triazin-2-yl]amino]benzonitrile; 4-[[4-amino-6-(2,4,6-trimethylphenoxy)-1,3,5-tri Azin-2-yl]amino]benzonitrile; 4-[[4-(hydroxylamino)-6-(2,4,6-trimethylphenoxy)-1,3,5-triazine-2- Base]amino]benzonitrile; 4-[[4-amino-6-[(2,4-dichloro-6-methylphenyl)amino]-1,3,5-triazin-2-yl]amino ]benzonitrile; 4-[[4-[(2,4-dichloro-6-methylphenyl)amino]-6-(hydroxylamino)-1,3,5-triazin-2-yl]amino ]benzonitrile; 4-[[4-(hydroxyamino)-6-(2,4,6-trichlorophenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile trifluoro Acetate (1:1); 4-[[4-(4-acetyl-2,6-dimethylphenoxy)-6-amino-1,3,5-triazin-2-yl] Amino]benzonitrile; 4-[[4-amino-6-(2,4,6-tribromophenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[ [4-amino-6-(4-nitro-2,6-dimethylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-amino -6-(2,6-dibromo-4-methylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-amino-6-(4 -formyl-2,6-dimethylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-amino-6-[(2,4- Dichlorophenyl)thio]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-[(5-acetyl-2,3-dihydro-7-methyl Base-1H-inden-4-yl)oxy]-6-amino-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-amino-6-[(4- Bromo-2-chloro-6-methylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-amino-6-[(2-chloro- 4,6-Dimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-amino-6-[[2,4-dichloro- 6-(trifluoromethyl)phenyl]amino]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-amino-6-[methyl(2,4, 6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-amino-6-[[2,6-dibromo-4- Methylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-amino-6-[[2,6-dibromo-4-(1- Methylethyl)phenyl]amino]-1,3,5-triazin-2-yl]amino]benzonitrile; their N-oxides, pharmaceutically acceptable addition salts and stereochemical isomers form.

Compounds of formula (I) can be prepared according to methods well known in the art.

Optionally in the presence of a suitable base such as sodium hydroxide, sodium hydride, triethylamine or N,N diisopropylethylamine etc., in for example 1,4-dioxane, tetrahydrofuran, 2-propanol, Formula (I') can especially be prepared by reacting an intermediate of formula (II) wherein ^W is a suitable leaving group such as halogen with an amino derivative of formula (III) in a reaction inert solvent such as N-methyl-pyrrolidone compound.

In this and subsequent preparations, the reaction product can be isolated from the reaction medium and, if necessary, further purified by methods well known in the art, such as extraction, crystallization, distillation, trituration and chromatography.

In the case where ^R contains a hydroxyl moiety, it is convenient to carry out the above reaction with intermediate (III) in protected form, so that the hydroxyl moiety bears a suitable protecting group P, for example a trialkylsilyl group, The protecting group is subsequently removed according to methods known in the art.

Compounds of formula (I') can also be conveniently prepared using solid phase synthesis techniques. Typically, solid phase synthesis involves reacting intermediates with polymeric supports during the synthesis. This intermediate-loaded polymer can then be subjected to multiple synthetic steps. After each step, impurities were removed by allowing the resin to be filtered and washed several times with different solvents. At each step, the resin can be cleaved to react with different intermediates in the next step, thus allowing the synthesis of many compounds. After the final step of the method, the resin is treated with a reagent or method to cleave the resin from the sample.

Suitable polymeric supports include, for example, Rink amide resins (Calbiochem-Novabiochem Corp., San Diego, CA).

For example, following the method described in Scheme 1, a compound of formula (I') wherein NR ¹ R ² is NH ₂ is prepared, which is represented by formula (I'-a).

Process 1

In scheme 1, in the presence of piperidine, in a suitable solvent such as N,N-dimethylformamide, Rink amide resin is reacted to obtain the primary amine of formula (IV-a), and then in a suitable solvent such as dimethylformamide It is further reacted with an intermediate of formula (V) wherein W ¹ is a suitable leaving group such as halogen in the presence of a base such as N,N-diisopropylethylamine in the presence of a base such as N,N-diisopropylethylamine. Impurities can be removed by washing several times with various solvents such as N,N-dimethylformamide, dichloromethane, dimethylsulfoxide, and the like. The resulting polymer bound intermediate of formula (IV-b) is then further reacted with LH(VI). To facilitate this transformation, silver triflate, sodium hexamethyldisilazide or cesium carbonate can be used. Finally the resin is treated with a cleaving agent such as trifluoroacetic acid in tetrahydrofuran, whereby compounds of formula (I') wherein ^NR1R2 is ^NH2 are obtained ^.

Additional compounds of formula (I') may be prepared by interconverting compounds of formula (I') following art-known group transformation reactions.

The above reactions specific to the preparation of compounds of formula (I') or subclasses thereof can also be applied to the preparation of compounds of formula (I).

Some intermediates as mentioned above are commercially available or can be prepared according to methods known in the art. Some of these preparation methods are described below.

By making an intermediate of formula (VII) wherein W ^is a suitable leaving group such as halogen in a reaction inert solvent such as tetrahydrofuran, 1,4-dioxane, etc., in the presence of a suitable base such as triethylamine Reaction with the amine derivative of formula (Ⅷ), then in the presence of a base such as potassium carbonate, sodium hydride, N, N-diisopropylethylamine, etc., in a reaction inert solvent such as acetonitrile, 1,4-dioxane The intermediate of formula (II) can be prepared by reacting the intermediate of formula (V) thus obtained with the intermediate of formula (VI) in a ring or the like.

具体的中间体为那些其中R^4’如在式(Ⅰ’)化合物中定义，R³为氢，A’为CH，W¹为卤素例如氯和溴并且L如在式(Ⅰ)化合物中定义的式(Ⅱ)中间体，条件是R⁵不为对氰基-苯基、对硝基-苯基、对甲氧基-苯基和对氨基羰基-苯基和R⁶不为2-(4-羟基苯基)乙基]氨基；更特别地，R³、A’和W¹如上定义，R^4’为氰基和L为-X-R⁵或-X-A1k-R⁶；其中R⁵和R⁶各独立为2，3-二氢化茚基、吲哚基或苯基；所述2，3-二氢化茚基、吲哚基或苯基的每一个可以两个、三个、四个或五个取代基取代，每一个取代基独立选自卤代、C_1-6烷基、C_1-6烷氧基、羟基、C_1-6烷基羰基、C_1-6烷氧基羰基、甲酰基、氰基、硝基、氨基和三氟甲基。The order of the above reaction process can also be reversed, that is, at first the intermediate of formula (VII) is reacted with the intermediate of formula (VI), and then, the intermediate of formula (IX) generated can be further reacted with the amine derivative of formula (Ⅷ) , thus forming an intermediate of formula (II).

Particular intermediates are those wherein R ^4' is as defined in compounds of formula (I'), R ³ is hydrogen, A' is CH, W ¹ is halogen such as chlorine and bromine and L is as defined in compounds of formula (I) The intermediate of formula (II), provided that R is ^not p-cyano-phenyl, p-nitro-phenyl, p-methoxy-phenyl and p-aminocarbonyl-phenyl and R is not ^2- ( 4-hydroxyphenyl) ethyl] amino; more particularly, R ³ , A' and W ¹ are as defined above, R ^4' is cyano and L is -XR ⁵ or -X-Alk-R ⁶ ; wherein R ⁵ and R are ^each independently 2,3-indanyl, indolyl or phenyl; each of said 2,3-indanyl, indolyl or phenyl can be two, three, four One or five substituents are substituted, and each substituent is independently selected from halo, C _1-6 alkyl, C _1-6 alkoxy, hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxy Carbonyl, formyl, cyano, nitro, amino and trifluoromethyl.

Compounds of formula (I&apos;) and some of said intermediates may have one or more stereocenters in their structure, present in the R or S configuration.

Compounds of formula (I') as prepared in the process described above may be synthesized as a mixture of stereoisomeric forms, especially in the form of a racemic mixture of enantiomers, which mixtures can be synthesized according to known art. split method to separate each other. The racemic compounds of formula (I) can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are subsequently separated, for example by selective or fractional crystallization, and the enantiomers are liberated therefrom by a base. Another method of separating enantiomeric forms of compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the correspondingly pure starting material in the appropriate stereochemically isomeric form, provided said stereospecific reaction occurs. If preference calls for a specific stereoisomer, said compounds will be synthesized by stereospecific methods of preparation. These methods advantageously use enantiomerically pure starting materials.

Compounds of formula (I), (I') and intermediates of formula (II) exhibit antiretroviral properties, especially anti-human immunodeficiency virus (HIV), which is the acquired immunodeficiency syndrome (AIDS) in humans etiological agents in. The HIV virus preferably infects human T-4 cells and destroys them or alters their normal function, especially the coordination of the immune system. As a result, infected patients have dwindling numbers of T-4 cells, and the cells behave abnormally. Consequently, the immune defense system is unable to fight off infections and tumors and the HIV-infected patients often die from opportunistic infections such as pneumonia or from cancer. Other disorders associated with HIV interference include thrombocytopenia, Kaposi's sarcoma, and infections of the central nervous system characterized by progressive demyelination, leading to dementia and symptoms such as progressive dysarthria, ataxia, and disorientation . HIV infection is additionally associated with peripheral neuropathy, progressive generalized lymphadenopathy (PGL), and AIDS-related complex (ARC).

Compounds of the invention also exhibit activity against HIV-1 strains with acquired resistance to non-nucleoside reverse transcriptase inhibitors known in the art. They also have little or no binding affinity for human alpha-1 acid glycoprotein.

Due to their antiretroviral properties, especially their anti-HIV properties, especially their anti-HIV-1 activity, the compounds of formula (I) or (I') or any subclass thereof, their N-oxides , pharmaceutically acceptable salts and stereochemical isomeric forms are used for the treatment of HIV-infected individuals and for the prophylaxis of such individuals. In general, the compounds of the invention are useful in the treatment of warm-blooded animals infected with viruses whose presence is mediated by or dependent on the enzyme reverse transcriptase. Diseases that can be prevented or treated with the compounds of the present invention, particularly those related to HIV and other pathogenic retroviruses, include AIDS, AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), and diseases caused by retroviruses. chronic CNS diseases such as HIV-mediated dementia and multiple sclerosis.

The compounds of the present invention or any subclass thereof such as compounds of formula (I') can thus be used as medicaments against the diseases mentioned above. Said use as a medicament or method of treatment includes the systemic administration to HIV-infected patients of an amount effective to combat diseases associated with HIV and other pathogenic retroviruses, especially HIV-1.

The compounds of the present invention, or any subgroup thereof, may be formulated into a variety of pharmaceutical forms for administration purposes. As suitable compositions there may be mentioned all compositions customary for the systemic administration of drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of a particular compound, optionally in the form of an addition salt, is mixed as the active ingredient in an intimate admixture with a pharmaceutically acceptable carrier, depending on the desired form of preparation for administration. , the vector can take a wide variety of forms. It is desirable that these pharmaceutical compositions be presented in dosage units particularly adapted for oral, rectal, subcutaneous or parenteral injection administration. For example, in the preparation of compositions in oral dosage form, any of the usual pharmaceutical media may be used, for example water, glycols, oils in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions. , alcohol, etc.; or solid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrants, etc. are used in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage units, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water (at least in large part), although other ingredients such as ingredients to aid dissolution may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose. Injection suspensions may also be prepared in which appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In compositions suitable for subcutaneous administration, the carrier optionally includes a penetration enhancer and/or a suitable wetting agent, optionally in admixture with suitable additives of any nature in minor proportions, which additives do not appear on the skin. produce significant adverse effects.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. . Examples of such dosage units are tablets (including scored or coated tablets), capsules, pills, powder sachets, wafers, injectable solutions or suspensions and the like, and discrete multiple units thereof.

From the experimental results shown herein, the skilled artisan can determine an effective daily dose in the treatment of HIV infection. Usually, the expected daily effective dose is 0.01 mg/kg to 50 mg/kg body weight, more preferably 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Such sub-doses may be formulated in unit dosage form, eg, containing 1 to 1000 mg and especially 5 to 200 mg of active ingredient per unit dosage form.

The precise dosage and frequency of administration will depend on the particular compound of formula (I) being used, the particular disease being treated, the severity of the disease being treated, the age, weight and general physical condition of the particular patient, and the available medical knowledge of the art for that individual. Depending on other drugs known to the skilled artisan. Furthermore, said effective daily dose may, of course, be lowered or increased depending on the response of the patient and/or according to the evaluation of the physician prescribing the compounds of this invention. Therefore, the effective daily dose range mentioned above is only a guideline.

Combinations of antiretroviral compounds and compounds of formula (I) or (I') or any subclass thereof can also be used as medicaments. Accordingly, the present invention also relates to a combined preparation comprising (a) a compound of formula (I) or (I') or any subgroup thereof and (b) another Products of antiretroviral compounds. The different drugs may be combined in a single formulation together with a pharmaceutically acceptable carrier. The other antiretroviral compounds may be known antiretroviral compounds such as nucleoside reverse transcriptase inhibitors, for example zidovudine (3'-azido-3'-deoxythymidine, AZT ), didanosine (dideoxyinosine, ddI), zalcitabine (dideoxycytidine, ddC) or lamivudine (3'-thio-2'-3'-dideoxycytidine, 3TC), etc.; non-nucleoside reverse transcriptase inhibitors such as suramin, sodium foscarnet (phosphonoformic acid trisodium salt), nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H- Dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one), sustiva (efavirenz), tacrine (tetrahydro-aminoacridine), etc. ; TIBO (tetrahydro-imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and thione) type compounds such as (S)-8-chloro -4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzo Diaza-2(1H)-thiones; compounds of the α-APA (α-anilinophenylacetamide) type such as α-[(2-nitro-phenyl)amino]-2,6-di Chlorobenzene-acetamide, etc.; TAT inhibitors such as RO-5-3335, etc.; protease inhibitors such as indinavir, ritanovir, saquinavir, etc.; NMDA receptor inhibitors such as pentamidine; α-glucosidase inhibitors such as Australian millet spermine, etc.; ribonuclease H inhibitors such as dextran (dextran sulfate), etc.; or immunomodulators such as levamisole, thymopentin, etc.

The following examples are intended to illustrate the invention. Experimental part A) Preparation of intermediates

Example A.1a) 2,4,6-Trichloro-1,3,5-triazine (0.07440 mol) and tetrahydrofuran (100 ml) were mixed and cooled to -75°C under an argon atmosphere. 4-Aminobenzonitrile (0.07440 mol) was added and the solution was stirred at -75°C for 4 hours. Triethylamine (0.07440 mol) was added dropwise and the reaction mixture was slowly warmed to room temperature and stirred for 3 days. After adding 1,4-dioxane (100ml), the resulting precipitate was collected by filtration, washed with tetrahydrofuran and dried to give 12.74g of 4-[(4,6-dichloro-1,3,5-triazine- 2-yl)amino]benzonitrile (interm. 1). b) NaH (0.0113 mol), _CH3CN (30 ml) and 2,6-dichlorophenol were mixed and stirred under argon atmosphere for 15 minutes. Intermediate (1) (0.0113 mol) was then added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with ice water (30ml) and filtered. A precipitate formed in the filtrate and was filtered off. The resulting solid was washed with _H2O and _CH3CN , then dried to give 0.62 g (14%) of 4-[[4-chloro-6-(2,6-dichlorophenoxy)-1,3, 5-Triazin-2-yl]amino]benzonitrile (Intermediate 2). c) Under argon flow, N,N-diisopropylethylamine (0.00714mol) was added to 2-chloro-6-methylaniline (0.00714mol) in 1,4-dioxane (20ml) in the solution. A solution of intermediate (1) (0.00714 mol) in 1,4-dioxane (5 ml) was added. The reaction mixture was stirred and refluxed for 24 hours. _The solvent was evaporated and _CH2Cl2 was added. The organic layer was washed with saturated aqueous NaHCO ₃ and the resulting precipitate was filtered off to give 0.56 g (21.1%) of 4-[[4-chloro-6-[(2-chloro-6-methylphenyl) Amino]-1,3,5-triazin-2-yl]amino]benzonitrile (interm. 3).

Example A.2a) 2,4,6-Trichloro-1,3,5-triazine (0.0266 mol) was added to 1,4-dioxane (50 ml) under argon atmosphere. The solution was stirred until it became homogeneous, then 2,6-dichloroaniline (0.0266 mol) and _K2CO3 ( _0.0362 mol) were added. The reaction mixture was stirred at room temperature for 3 days. The solvent was evaporated. Water was added to the residue and the _aqueous phase was extracted with _CH2Cl2 . The separated organic layer was washed with brine, dried over potassium carbonate, filtered and the filtrate was evaporated to give 7.52 g (91.2%) of N-(2,6-dichlorophenyl)-4,6-dichloro-1,3 , 5-Triazin-2-amine (Intermediate 4). b) Under argon atmosphere, 1,4-dioxane (50ml), 4-cyano-aniline (0.0243mol) and N,N-diisopropylethylamine (0.0243mol) were added to the intermediate (4) (0.0243 mol). The reaction mixture was stirred and refluxed for one week. The reaction was cooled, the solvent was evaporated and the residue was dissolved in ethyl acetate. The organic phase was washed with saturated aqueous NaHCO ₃ and with brine, dried over potassium carbonate, filtered and the solvent was evaporated. The residue was stirred in a mixture of _CH2Cl2 and saturated _NaHCO3 , and the precipitate was filtered off, yielding 2.26 g (23.8%) of 4-[[4-chloro-6-[(2,6 _- dichlorophenyl )amino]-1,3,5-triazin-2-yl]amino]benzonitrile (interm. 5).

Example A.3

Rink amide resin (15 g; Calbiochem-Novabiochem, San Diego, CA, Product _No. 01-64-0013) was washed with _CH2Cl2 (100 ml), N,N-dimethylformamide (200 ml) in a reaction vessel And N,N-dimethylformamide:piperidine (150ml:50ml) was added. The mixture was stirred for ₂ hours, washed with N,N-dimethylformamide, _CH2Cl2 and dimethylsulfoxide. Intermediate (1) (0.06mol), N,N-diisopropylethylamine (10.5ml) and dimethyl sulfoxide (200ml) were added and the reaction mixture was stirred for three days, then N,N- Washing with dimethylformamide and _CH2Cl2 afforded _the resin bound intermediate (1).

Table 1 lists the intermediates which were prepared according to one of the above examples.

中间体编号 实施例编号     X     R^a     R^b R^c R^d 物理数据  2356789101112131415161718192021222324  A1bA1cA2bA2bA1cA1cA1cA1cA1cA1cA1cA1cA2bA1cA1cA1bA2bA2bA1cA2bA2bA1c  -O--NH--NH--NH--NH--NH--NH--NH--NH--NH--NH--NH--NH--S--NH--O--NH--NH--NH-NH--NH--NH--NH-NH-     ClClClCH₃CH(CH₃)₂CH₃C₂H₅C(=O)CH₃CH₃CH₃C₂H₅BrClClCH₃ClC1CF₃CH₃BrBrCl     HHHHHCH₃HHBrCH₃HFClHHClCF₃ClCH₃CH₃异丙基Cl  HHHHHHHCH₃HBrHHHHClHHHHHHH  ClCH₃ClCH₃CH₃CH₃C₂H₅HCH₃CH₃CH₃FClClCH₃ClClClCH₃BrBrCl mp 295-296℃mp 142-143℃mp 238-239℃mp 247-248℃mp 275-276℃mp 178-179℃mp 283-284℃mp 263-264℃mp 252-253℃ B.式(Ⅰ’)化合物的制备Table 1

Intermediate number Example number x R ^a R ^b R ^c R ^d physical data 2356789101112131415161718192021222324 A1bA1cA2bA2bA1cA1cA1cA1cA1cA1cA1cA1cA2bA1cA1cA1bA2bA2bA1cA2bA2bA1c -O--NH--NH--NH--NH--NH--NH--NH--NH--NH--NH--NH--NH--S--NH--O--NH --NH--NH-NH--NH--NH--NH-NH- ClClClCH ₃ CH(CH ₃ ) ₂ CH ₃ C ₂ H ₅ C(=O)CH ₃ CH ₃ CH ₃ C ₂ H ₅ BrClClCH ₃ ClClCF ₃ CH ₃ BrBrCl _{HHHHHCH3HHBrCH3HFClHHClCF3ClCH3CH3IsopropylCl _ _ _ _} HHHHHHHCH ₃ HBrHHHHClHHHHHHH ClCH ₃ ClCH ₃ CH ₃ CH ₃ C ₂ H ₅ HCH ₃ CH ₃ CH ₃ FClClCH ₃ ClClClCH ₃ BrBrCl mp 295-296℃mp 142-143℃mp 238-239℃mp 247-248℃mp 275-276℃mp 178-179℃mp 283-284℃mp 263-264℃mp 252-253℃ B. Preparation of Compound of Formula (I')

Example B.1a) A mixture of intermediate (8) (0.00137 mol) and _NH3 in 1,4-dioxane (0.5M; 0.00548 mol) was heated in a pressure vessel at 100°C for 6 days . The solvent was evaporated and the residue was dissolved in _CH2Cl2 , washed with saturated aqueous _NaHCO3 , dried, filtered _and the solvent was evaporated. The residue was purified by _column chromatography on silica gel (eluent: _CH2Cl2 / _CH3OH 100/0, 99/1 and 98/2). The desired fractions were collected and the solvent was evaporated. The residue was recrystallized from toluene. The precipitate was filtered off and dried to yield 0.29 g (61.4%) of 4-[[4-amino-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazine- 2-yl]amino]benzonitrile (Compound 9). b) As an alternative method for preparing compound (9), intermediate (8) (0.0230 mol) in NH ₃ (2.0 M, 60 ml) in 2-propanol and 1, A mixture of _NH3 (0.5M, 20ml) in 4-dioxane was heated for 21 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate, washed with 1N NaOH, water and brine, dried, filtered and the filtrate was evaporated. The residue was recrystallized from acetonitrile to obtain 5.25 g (66.1%) of compound (9). c) Intermediate (21) (0.00150 mol) and 0.5M _NH3 in 1,4-dioxane (0.015 mol) were added to a pressure bottle. The reaction mixture was heated to 40 °C. After 5 days, the reaction was cooled to room temperature. 2.0M _NH3 in 2-propanol (0.015 mol) was added and the reaction was brought to 40°C. The reaction was diluted with ether and extracted with cold 1M NaOH. The aqueous layer was extracted two more times and the organic phases were combined. The insoluble material was filtered off and washed with ether, which dissolved most of the material in the filtrate. The filtrate was combined with the organic phase and the solution was dried, filtered and the solvent was evaporated. The residue was purified by flash chromatography _on silica gel, eluting with 4:1 _CH2Cl2 : ether to 100% ether. The resulting material was recrystallized in THF/ _CH3CN , the precipitate was filtered off and dried to give 0.36 g (67%) of 4-[[4-amino-6-[(2,4,6-trimethylphenyl )azo]-1,3,5-triazin-2-yl]amino]benzonitrile (compound 69).

Example B.2

O-(Trimethylsilyl)-hydroxylamine (0.0282 mol) was added to intermediate (5) (0.00282 mol) in 1,4-dioxane (10 ml). The reaction mixture was stirred at room temperature for two days. The solvent was evaporated. The residue was dissolved in ethyl acetate, washed with 1N HCl, saturated aqueous NaHCO ₃ and brine, dried, filtered and the solvent was evaporated. Through silica gel column chromatography ((I) elution gradient: CH ₂ Cl ₂ /CH ₃ OH 98/2 to 96/4 and (II) eluent: CH ₂ Cl ₂ /CH ₃ OH 100/0, 99 /1 and 98/2) to purify the residue. The desired fractions were collected and the solvent was evaporated. The residue was recrystallized from acetonitrile. The precipitate was filtered off and dried to yield 0.32 g (29.2%) of 4-[[[6-(2,6-dichlorophenylamino)-4-(hydroxylamino)]-1,3,5-triazine- 2-yl]amino]benzonitrile (Compound 4).

Example B.3

Tetrahydrofuran (10 ml) and 2,5-dimethyl-phenol (0.00818 mol) were added to NaH (0.00859 mol). The mixture was stirred at room temperature for 30 minutes. A solution of intermediate (1) (0.00818 mol) in tetrahydrofuran (100 ml) was then added. The reaction mixture was stirred for 16 hours. The solvent was then evaporated and _NH3 in 1,4-dioxane (50ml) was added. The resulting reaction mixture was stirred for 16 hours. The solvent _was evaporated and the resulting residue was treated with _H2O / _CH2Cl2 , stirred and filtered. A precipitate formed in the filtrate and was filtered off, yielding 0.42 g of Fraction 1 . The resulting filtrate was dried _{over K2CO3} and concentrated. The residue was purified by flash column chromatography (eluent: _CH3OH / _{CH2Cl2 2.5} /97.5). The desired fractions were collected and the solvent was evaporated, yielding 2.89g of Fraction 2. Fractions 1 and 2 were combined and recrystallized from _CH3CN . The precipitate was filtered off and dried, yielding 1.16 g (42.7%) of 4-[[4-amino-6-(2,5-dimethylphenoxy)-1,3,5-triazin-2-yl] Amino]benzonitrile (Compound 2).

Example B.4

Under argon, the resin-bound intermediate (1) as prepared in Example A3 (0.00015 mol), silver triflate (0.075 g) in dimethylsulfoxide (1 ml) was added to the reaction vessel. solution in , 4-bromo-2-chloro-6-methyl-phenol (0.0027mol), dimethylsulfoxide (3ml), 1.0M bis(trimethylsilyl)sodium amide and disilyl Amine (1,1,1-Trimethyl-N-(trimethylsilyl)-silylamine, sodium salt) (3 ml). The reaction mixture was heated at 95°C for 12 hours. The sample was filtered and _the resin was washed with N,N-dimethylformamide (3X), _CH2Cl2 , N,N-dimethylformamide, _{CH3OH and CH2Cl2} (3X). Samples were lysed twice (5 ml, then 3 ml) with 10% trifluoroacetic acid _{in CH2Cl2} . The solvent was evaporated under _N2 . Purification by reverse phase HPLC afforded 0.0055 g of 4-[[4-amino-6-(4-bromo-2-chloro-6-methylphenoxy)-1,3,5-triazin-2-yl ]amino]benzonitrile (Compound 33).

Example B.5

Under argon, the flask was charged with resin-bound intermediate (1) as prepared in Example A3 (0.00015 mol), CsCO ₃ (0.975 g, 4-chloro-2,6-dimethylphenol (0.0038 mol), dimethylsulfoxide (2ml) and 1ml of a solution of silver trifluoromethanesulfonate (0.075g) in dimethylsulfoxide (1ml). Bubble argon into the reaction mixture for 1 minute. At The flask was heated at 95°C for 20 hours. The sample was then filtered and washed with N,N-dimethylformamide (2X), water (3X), N,N-dimethylformamide (2X), CH ₃ OH (1X) and _CH2Cl2 (3X) _.The sample was then cleaved with 10% trifluoroacetic acid in _CH2Cl2 (3ml) to give 0.0043g of 4-[[4-amino _- 6-(4 -Chloro-2,6-dimethylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile (compound 36).

Example B.6

To the flask was added intermediate (1) (0.00752 mol), N,2,4,6-trimethyl-aniline (0.00752 mol) in 1,4-dioxane (20 ml) under argon and N,N-diisopropylethylamine (0.00752 mol). The reaction mixture was stirred and refluxed for 20 hours and the solvent was evaporated. The residue was transferred to a pressure vessel containing 0.5M _NH3 (0.005mol) in 1,4-dioxane and 2.0M _NH3 (0.040mol) in 2-isopropanol and heated at 115°C The mixture was heated for 24 hours. The solvent was evaporated, the residue was dissolved _{in CH2Cl2} , washed with 1N NaOH and water, dried over potassium carbonate, filtered and the solvent was evaporated. The residue was recrystallized twice from acetonitrile. Filtration and drying yielded 1.0 g (37%) of 4-[[4-amino-6-[methyl(2,4,6-trimethylphenyl)amino]-1,3,5-triazine -2-yl]amino]benzonitrile (compound 73).

Example B.7

Dissolve 4,6-dichloro-N-(2,6-dibromo-4-methylphenyl)-1,3,5-triazin-2-amine (0.00651mol) in 1,4-diox Hexacyclic (30ml). Subsequently, 4-amino-benzonitrile (0.0066 mol) and N,N-diisopropylethylamine (0.0066 mol) were added, and the clear solution was heated to reflux for 4 days. The reaction was cooled to room temperature overnight. The mixture was diluted with ethyl acetate and treated with cold 1M NaOH. The layers were separated and the organic phase was extracted again with fresh 1M NaOH. The combined aqueous phases were treated with solid NaOH to maintain pH >10 and backwashed with ethyl acetate (2X). The combined organic phases were dried, filtered and concentrated. The residue was separated and purified by flash column chromatography on silica gel ( _eluent : _CH2Cl2 ). The desired fractions were combined, treated with _CH3CN , triturated with _CH3CN , filtered off and dried to yield 0.30 g (8.0%) of N,N'-[6-[(2,6-dibromo-4- Methylphenyl)amino]-1,3,5-triazine-2,4-diyl]bis[4-amino-benzonitrile] (compound 74).

Example B.8

Under argon, intermediate (1), 1-(2,3-dihydro-4-hydroxy-7-methyl-1H-inden-5-yl)-ethanone, _{Cs2CO 3} and 1,4-dioxane and heated at 100 °C for 48 h while rotating the sample slightly. The sample was cooled and _NH3 in isopropanol was added. The reaction was heated in a sealed tube at 100°C for 48 hours. The reaction was cooled and water (3ml) was added to dissolve the _Cs2CO3 , a sample was filtered and purified by HPLC to give 4-[[4 _- [(5-acetyl-2,3-dihydro-7-methyl -1H-inden-4-yl)oxy]-6-amino-1,3,5-triazin-2-yl]amino]benzonitrile (compound 84).

Tables 2 and 3 list compounds of formula (I) prepared according to one of the above Examples.

Table 2 Compound number Example number x R ¹ R ^a R ^b R ^c R ^d R ^e melting point; salt form 12345678910111213141516171819202122232425 B1aB3B3B2B2B1aB1aB1aB1a or B1bB1cB2B1cB1cB1bB1bB1bB1bB1bB1bB2B1aB1aB2B1bB2 -O--O--O--NH--NH--NH--NH--NH--NH--NH--NH--NH--NH--NH--NH--NH--NH --NH--S--S--NH-NH-NH-NH-NH--O--O- HHHOHOHHHHHHOHHHHHHHHHHOHHHOHHOH ClCH ₃ CH ₃ ClCH ₃ CH ₃ ClCH(CH ₃ ) ₂ CH ₃ ClCH ₃ C ₂ H ₅ C(=O)CH ₃ CH ₃ CH ₃ C ₂ H ₅ BrClClClClClCH ₃ CH ₃ HHHHHHHHHHHHHHHHHHHHHHHHHHH _{HHHHHHHHCH3HCH3HHBrCH3HFClHHClHClCH3CH3 _ _ _ _} HCH ₃ HHHHHHHHHHHCH ₃ HBrHHHHHHHHHH ClHCH ₃ ClCH ₃ CH ₃ CH ₃ CH ₃ CHxClCH ₃ C ₂ H ₅ HCH ₃ CH ₃ CH ₃ FClClClClClCH ₃ CH ₃ 278-279°C 193-194°C 235-236°C 235-236°C 207-210°C HCl (1:1) 242-244°C HCl (1:1) 130-131°C 253-254°C 151-152°C 144- 145°C 247-248°C 273-274°C 255-256°C 221-222°C 158-159°C 222-223°C 233-234°C 224-225°C 293-294°C 145-147°C 258-259°C 246-247°C 262-263℃236-237℃221-222℃ 262728293031323334353637383940414243444546474849505152535455565758596061626364656667 B2B1bB1bB2B1aB2B2B4B4B4B5B5B5B5B5B5B5B5B5B5B5B5B5B5B5B5B5B5B5B5B5B5B5B5B5B5B5B8B8B8B8B8B8 NH-NH-NH--NH--NH--O--NH--O--O--O--O--O--O--O--O--O--O--O --O--O--O--O--O--O--O--O--O--O--O--S--S--S--S--S-- S--O--NH--O--NH--NH--NH--NH--NH- OHHHOHHOHOHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ClClCH ₃ ClClCH ₃ ClClClCH ₃ CH ₃ CH ₃ ClC(=O)CH ₃ BrCH ₃ ClClFClOCH ₃ OCH ₃ BrC(=O)CH ₃ BrBrCH ₃ ClClClFCH ₃ CH ₃ CH ₃ CH ₃ CH ₃ ClC ₂ H ₅ ClClF _{HHHHHHHHHHHHHHHHHClClHHHHCH3HCH3HCH - CH3HHHHHHHHHHHHHF} ClCH ₃ HClClHClBrClC(=O)CH ₃ ClBrClClBrNO ₂ ClHFFHCNClFBrCH ₃ ClClClFClFCH ₃ CH ₃ ICH ₃ CH ₃ BrBrCH ₃ FF _{HHClHHClHHHHHHHHHHClHHHHHCH3HCH3HHCH3HHClHHHHNH2HHHHCH3F _ _ _} ClClCH ₃ CH ₃ ClCH ₃ ClCH ₃ CH ₃ CH ₃ CH ₃ CH ₃ HClBrCH ₃ ClClFClOCHHBrFBrBrCH ₃ CH ₃ HHHHCH ₃ HCH _{3 CH 3 HCH 3 C 2 H 5} CHHF 75-176℃224-226℃230-231℃268-269℃260-261℃174-175℃153-154℃ 686970717273747576777879808182 B8B1cB1bB1bB1bB7B7B1bB1bB5B5B8B8B8 -NH--N=N--NH--NH--NH--N(CH ₃ )--NH--NH--NH--NH--O--O--O--O--NH - HHHHHH p-cyanophenyl p-cyanophenyl HHHHHHH OCH ₃ CH ₃ ClCF ₃ BrCH ₃ BrBrBrBrCH ₃ CH ₃ FNH ₂ C(=O)OCH ₃ HHHHHHHHHHHHHFHH OCH ₃ CH ₃ CF ₃ ClBrCH ₃ CH _{3isopropylCH 3isopropylNH 2} C(=O)HOHClOCH ₃ HHHHHHHHHHHHFCH ₃ OCH ₃ OCH ₃ CH ₃ ClClBrCH ₃ BrBrBrBrCH ₃ CH ₃ FClOCH ₃ 315℃152-154℃158-160℃167-169℃251-252℃332-333℃315-316℃238-239℃158-160℃

C.药理学实施例table 3

C. Pharmacological Examples

Example C.1

在此(OD_r)_HIV为采用在HIV感染的细胞中给定浓度的受试化合物测量的光密度；(OD_c)_HIV为对于对照的、未处理的HIV感染的细胞测量的光密度；(OD_c)_模拟品为对于对照的、未处理的模拟品感染的细胞测量的光密度；所有光密度值在540nm下测定。按照以上公式达到50％保护率的剂量定义为50％抑制浓度(IC₅₀以μM表示)。CC₅₀对IC₅₀的比率定义为选择性指数(SI)。式(Ⅰ)化合物显示有效地抑制HIV-1。具体的IC₅₀、CC₅₀和SI值列在下表4中。Rapid, Sensitive and Automated Test Method for In Vitro Evaluation of Anti-HIV Drugs. HIV-1 (wild-type IIIB) transformed T4-cell line, MT-4, was used as a target cell line. are highly sensitive and allow HIV infection. Inhibition of HIV-induced cytopathic effects was used as an endpoint. Spectrophotometric evaluation of HIV and mock-infected cells by in situ reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability. The 50% cytotoxic concentration (CC ₅₀ expressed in [mu]M) is defined as the concentration of compound which reduces the uptake of mock-infected control samples by 50%. The percent protection achieved by the compounds in HIV-infected cells was calculated by the following formula:

Here (OD _r ) _HIV is the optical density measured with a given concentration of test compound in HIV-infected cells; (OD _c ) _HIV is the optical density measured for control, untreated HIV-infected cells; ( OD _c ) _mock is the optical density measured for control, untreated mock-infected cells; all optical density values are determined at 540 nm. The dose to achieve 50% protection rate according to the above formula was defined as 50% inhibitory concentration (IC ₅₀ expressed in μM). The ratio of _CC50 to _IC50 was defined as selectivity index (SI). Compounds of formula (I) have been shown to effectively inhibit HIV-1. Specific _IC50 , _CC50 and SI values are listed in Table 4 below.

Table 4 Compound number _IC50 (μM) _CC50 (μM) Si 12345678910111213141516171819202122232830313334 0.0030.0030.0030.0020.0020.0040.0050.1650.0010.0030.0010.0210.2590.0030.0030.0060.0030.0080.0040.0030.0010.0030.0010.00010.00050.0002 ＞2034.933.88.07.840.349.99.344.06.16.330.0＞10037.31.78.153.845.640.611.727.8＞1007.642.863.59.9＞10.04.8 ＞645110750108994187345811518101875633826202244801449＞38611844498137216311603311285372627789＞3333376149106264881980＞47613658 Compound number _IC50 (μM) _CC50 (μM) Si 44454647484950515253545556575859606162636465666768697071 0.0050.0070.0310.0750.0190.0760.0590.0020.0030.0170.0040.0040.0050.0150.0030.0020.0030.0050.0030.0030.0140.0010.0960.110010.050.050.015 ＞100.152.9＞100.0＞100.08.7＞99.98.11.71.92.557.3＞99.962.6＞100.047.148.545.594.651.648.046.548.5＞99.945.663.9＞99.915.68.2 >196077258>3205>1340456>130813985963914213349>2777713059>6711162442697515172205491911016561339380824>10374124173>15474471860 353637383940414243 0.0010.0030.0010.007>100.0050.0020.0330.009 32.17.67 6>100.0<10>10.012.2>10.043.9 2471221795035>140841>18516102>3034668

727374757677787980 0.0020.0030.1900.3780.0010.0037.830.00785.5 6.551.77.037.85.947.047.030.0＞85.5 32591616437100118481743164534＞1

Compound number _IC50 (μM) _CC50 (μM) SI 818283 2.681.490.473 ＞99.199.659.6 ＞3767126

Compound number _IC50 (μM) _CC50 (μM) Si 8485 0.0010.413 54.153.7 45129130 D． Composition buy example

The following formulations illustrate typical pharmaceutical compositions of this invention suitable for systemic administration to animals and humans.

"Active ingredient" (A.I.) as used in these examples relates to compounds of formula (I) or their pharmaceutically acceptable addition salts. Example D. 1: Preparation of film-coated tablet cores

Will 100gA. I． , a mixture of 570 g lactose and 200 g starch was mixed thoroughly and thereafter wetted with a solution of 5 g sodium lauryl sulfate and 10 g polyvinylpyrrolidone in about 200 ml water. The wet powder mixture is sieved, dried and sieved again. Then 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil were added. The whole is mixed thoroughly and compressed into tablets to give 10,000 tablets, each containing 10 mg of the active ingredient. coating

To a solution of 10 g of methylcellulose in 75 ml of denatured ethanol was added a solution of 5 g of ethylcellulose in 150 ml of dichloromethane. Then 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol were added. Melt and dissolve 10 g of polyethylene glycol in 75 ml of dichloromethane. The latter solution is added to the former solution, followed by 2.5 g of magnesium stearate, 5 g of polyvinylpyrrolidone and 30 m thick of the colored suspension and the whole is homogenized. In the coating unit, the tablet cores are coated with the mixture thus obtained.

Claims (25)

1. Compounds of the following formula, their N-oxides, pharmaceutically acceptable addition salts or stereochemical isomeric forms are used in the preparation of medicines for treating patients with HIV (human immunodeficiency virus) infection:

Wherein A is CH, CR ^or N; n is 0, 1, 2, 3 or ⁴ ; R and ^R are each independently selected from hydrogen, hydroxyl, C _1-12 alkyl, C _1-12 alkoxy , C _1-12 alkylcarbonyl, C _1-12 alkoxycarbonyl, aryl, amino, mono- or bis (C _1-12 alkyl) amino, mono- or bis (C _1-12 alkyl) amino Carbonyl, wherein each of the previously mentioned C _1-12 alkyl groups can be optionally and independently selected from one or two independently selected from hydroxyl, C _1-6 alkoxy, hydroxy C _1-6 alkoxy, Substituents of carboxyl, C _1-6 alkoxycarbonyl, cyano, amino, imino, aminocarbonyl, aminocarbonylamino, mono- or bis (C _1-6 alkyl) amino, aryl and Het; or R ¹ and R ² together can form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or bis (C _1-12 alkyl) amino C _1-4 alkylene; R ³ is hydrogen, Aryl, C _1-6 alkylcarbonyl, C _1-6 alkyl, C _1-6 alkoxycarbonyl, C _1-6 alkyl substituted with C _1-6 alkoxycarbonyl; and each R ⁴ independently is hydroxyl, halo, C _1-6 alkyl, C _1-6 alkoxy, cyano, aminocarbonyl, nitro, amino, trihalomethyl or trihalogenmethoxy; L is -XR ⁵ or -X-Alk-R ⁶ ; wherein R ⁵ and R ⁶ are each independently 2,3-indanyl, indolyl or phenyl; said 2,3-indanyl, indolyl or benzene Each of the groups can be one, two, three, four or five independently selected from halo, C _1-6 alkyl, C _1-6 alkoxy, hydroxyl, C _1-6 alkylcarbonyl , C _1-6 alkoxycarbonyl, formyl, cyano, nitro, amino and trifluoromethyl; and X is -NR ₃ -, -NH-NH-, -N=N-, -O-, -S-, -S(=O)- or -S(=O) ₂ -; aryl is phenyl or one, two, three, four or five independently selected from halogen Substituent, C _1-6 alkyl, C _1-6 alkoxy, cyano, nitro and trifluoromethyl substituent substituted phenyl; Het is aliphatic or aromatic heterocyclic group; the aliphatic The heterocyclic group is selected from pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and tetrahydrothiophenyl, wherein each of the aliphatic heterocyclic groups can be optionally substituted by oxo and the aromatic heterocyclic group is selected from pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl, wherein each of the aromatic heterocyclic groups can be optionally Substituted by hydroxyl. 2. As the use of the compound claimed in claim 1, wherein L is -XR ⁵ , wherein R ⁵ is phenyl or independently selected from one, two, three, four or five halo, C _{1- 6} alkyl, C _1-6 alkoxy, cyano, C _1-6 alkylcarbonyl, nitro and trifluoromethyl substituent substituted phenyl. 3. Use of a compound as claimed in claim 1 or 2, wherein n is 1 and R ⁴ is cyano substituted at position 4 relative to said NR ³ moiety. 4. As in any one of claims 1 to 3, wherein L comprises two, three, four or five each independently selected from halogenated, hydroxyl, C _1-6 alkyl, C ₁ A phenyl group substituted by a substituent of _-6 alkoxy, C _1-6 alkoxycarbonyl, cyano, amino, trifluoromethyl, nitro, C _1-6 alkylcarbonyl and formyl. 5. ^Use as in any one of claims 1 to 4, wherein R and ^R are each independently selected from hydrogen, aryl or hydroxy. 6. Compound of formula:

wherein said variables R ¹ , R ² , R ³ and L are as defined in formula (I) of claim 1; and A' is CH or N; R ^4' is cyano, aminocarbonyl, nitro or trifluoro Methyl; with the proviso that when R4 ^' is cyano, ^R3 is hydrogen, and L is ^-XR5 where X is NH and ^R5 is 4-cyanophenyl or 4-iodophenyl, then ^NR1 R ² is not NH ₂ , NH[CH ₂ CH ₂ N(C ₂ H ₅ ) ₂ ], N(C ₂ H ₅ ) ₂ , NHCH ₃ , NHC ₂ H ₅ , or NH(4-cyano-phenyl) ; when R ^4' is trifluoromethyl, R ³ is hydrogen, and L is -XR ⁵ where X is NH and R ⁵ is 4-trifluoromethylphenyl, then NR ¹ R ² is not NH ₂ or N[(CH ₂ ) ₆ CH ₃ ] ₂ ; when R ^4' is nitro, R ³ is hydrogen or methyl, L is where X is NH or N-CH ₃ and R ⁵ is 4-fluorophenyl, 2 , 6-dimethylphenyl, 4-methylphenyl or 4-nitrophenyl -XR ⁵ , then NR ¹ R ² is not NH aryl, NCH ₃ aryl, N(aryl) ₂ , NH ₂ , NH[CH ₂ CH ₂ N(C ₂ H ₅ ) ₂ ], NH[CH ₂ CH ₂ N(CH ₃ ) ₂ ], NH[CH ₂ C(=O)OC ₂ H ₅ ], NH [CH ₂ C(=O)OH] or N(C ₂ H ₅ ) ₂ ; when R ^4' is nitro, R ³ is hydrogen, L is where X is S(O) ₂ or S and R ⁵ are benzene When -XR ⁵ of 4-chlorophenyl group or 4-chlorophenyl, then R ¹ and R ² are not aryl or C _1-12 alkyl substituted with one or more carboxyl groups; their N-oxides, pharmaceutically acceptable Addition salts and stereochemical isomeric forms. 7. As the compound claimed in claim 6, wherein L is -XR ⁵ , wherein R ⁵ is phenyl or independently selected from one, two, three, four or five halo, C _1-6 alkane A phenyl group substituted by substituents of radical, C _1-6 alkoxy, cyano, C _1-6 alkylcarbonyl, nitro and trifluoromethyl. 8. Compounds as claimed in claim 6 or 7, wherein R ^4' is aminocarbonyl, trifluoromethyl or cyano and L is 2,3,4,5,6-pentachloro-phenoxy, 2,3 , 5,6-tetrafluoro-4-hydroxy-phenoxy, 2,3,6-trichloro-phenoxy, 2,4,6-tribromo-3,5-dimethyl-phenoxy, 2,4,6-Tribromo-phenoxy, 2,4,6-trichloro-phenoxy, 2,4,6-trifluoro-phenoxy, 2,4,6-trimethyl-benzene Oxygen, 2,4-dichloro-3,5,6-trimethyl-phenoxy, 2,4-dichloro-6-methyl-phenoxy, 2,4-dichloro-phenoxy , 2,4-dimethyl-phenoxy, 2,5-dimethyl-phenoxy, 2,6-dibromo-4-chloro-3,5-dimethyl-phenoxy, 2, 6-Dibromo-4-methyl-phenoxy, 2,6-dichloro-4-fluoro-phenoxy, 2,6-dichloro-phenoxy, 2,6-dimethoxy-benzene Oxygen, 2,6-dimethyl-4-nitro-phenoxy, 2,6-dimethyl-phenoxy, 2-acetyl-4,6-dichloro-phenoxy, 2- Acetyl-4,6-difluoro-phenoxy, 2-amino-4,6-dichloro-5-methyl-phenoxy, 4-acetyl-2,6-dimethyl-phenoxy , 4-amino-2,6-dimethyl-phenoxy, 4-bromo-2,6-dimethyl-phenoxy, 4-bromo-2-chloro-6-methyl-phenoxy, 4-chloro-2,3,6-trimethyl-phenoxy, 4-chloro-2,6-dimethyl-phenoxy, 4-cyano-2-methoxy-phenoxy, 4 -Formyl-2,6-dimethyl-phenoxy, 4-iodo-2,6-dimethyl-phenoxy, 2,3,4,5,6-pentafluoro-anilino, 2 , 3,4-trimethoxy-6-(methoxycarbonyl)-anilino, 2,4,6-tribromo-anilino, 2,4,6-trichloro-anilino, 2,4,6 -Trimethoxy-anilino, 2,4,6-trimethyl-anilino, 2,4-dichloro-6-methyl-anilino, 2,4-dichloro-6-trifluoromethyl- Anilino, 2,6-dibromo-4-isopropyl-anilino, 2,6-dibromo-4-methyl-anilino, 2,6-dichloro-4-trifluoromethyl-anilino , 2,6-dichloro-anilino, 2,6-diethyl-anilino, 2,6-dimethyl-anilino, 2-acetyl-5-methyl-anilino, 2-bromo-anilino 4,6-difluoro-anilino, 2-chloro-4,6-dimethyl-anilino, 2-chloro-4-fluoro-5-methyl-anilino, 2-chloro-6-methyl- Anilino, 2-ethyl-6-methyl-anilino, 2-isopropyl-6-methyl-anilino, 3-amino-2,4,6-trimethyl-anilino, 3-bromo -2,4,6-trimethyl-anilino, 3-chloro-2,6-dimethyl-anilino, 4-bromo-2,6-diethyl-anilino, 4-bromo-2, 6-Dimethyl-anilino, 4-bromo-2-chloro-6-methyl-anilino, 4-methyl-anilino, N-methyl-2,4,6-trimethyl-anilino , 2,4,5-trichloro-phenylthio, 2,4,6-trimethyl-phenylthio, 2,4-dichloro-phenylthio, 2,4-difluoro-phenylthio, 2,4-Dimethyl-phenylthio, 2,6-dichloro-phenylthio, 2-chloro-4-fluoro-phenylthio, 2,4,6-trichloro-phenylhydrazino, 2 , 6-dichloro-phenylhydrazino, 2,4-dichloro-6-methyl-benzylamino, 2,4-dimethoxy-benzylamino, indol-4-yl-oxyl or 5-Acetyl-7-methyl-2,3-indan-4-yl-oxyl. 9. A compound as claimed in any one of claims 6 to 8, wherein ^R4 is cyano, L is ^-XR5 and ^R5 is not 4-cyanophenyl or 4-iodophenyl. 10. As in any one of claims 6 to 9, wherein L comprises phenyl substituted with two, three, four or five substituents, each substituent being independently selected from halo, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxycarbonyl, cyano, amino, trifluoromethyl, nitro, C _1-6 alkylcarbonyl and formyl. 11. A compound as claimed in any one of claims 6 to 10, wherein L is -XR ⁵ , wherein X is -NR ³ -, -NH-NH-, -N=N- or -O- and R ⁵ is 2 , 3-indanyl, indolyl or phenyl; each of said 2,3-indanyl, indolyl or phenyl can be independently two, three, four or five selected from halo, C _1-6 alkyl, C _1-6 alkoxy, hydroxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, formyl, cyano, nitro, amino and The substituent of trifluoromethyl is substituted. 12. A compound as claimed in any one of claims 6 to 11, wherein A' is CH, R ^4' is cyano, X is -O- or -NH- and R ⁵ or R ⁶ is two or three Phenyl substituted by substituents each independently selected from halo, C _1-6 alkyl, C _1-6 alkylcarbonyl, formyl, nitro or cyano. 13. As the compound claimed in claim 6, wherein said compound is: 4-[[4-amino-6-(2,6-dimethylphenoxy)-1,3,5-triazine-2- Base]amino]benzonitrile; 4-[[4-amino-6-[(2-chloro-6-methylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile ; 4-[[4-amino-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[ 4-(Hydroxyamino)-6-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4 -amino-6-[(2-ethyl-6-methylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-amino-6- [(2,6-dichlorophenyl)thio]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-(hydroxylamino)-6-[(2, 4,6-trichlorophenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-amino-6-(2,4,6-trimethyl Phenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-(hydroxylamino)-6-(2,4,6-trimethylphenoxy) -1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-amino-6-[(2,4-dichloro-6-methylphenyl)amino]-1, 3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-[(2,4-dichloro-6-methylphenyl)amino]-6-(hydroxylamino)-1, 3,5-Triazin-2-yl]amino]benzonitrile; 4-[[4-(hydroxylamino)-6-(2,4,6-trichlorophenoxy)-1,3,5-tri Oxyzin-2-yl]amino]benzonitrile trifluoroacetate (1:1); 4-[[4-(4-acetyl-2,6-dimethylphenoxy)-6-amino-1 , 3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-amino-6-(2,4,6-tribromophenoxy)-1,3,5-triazine- 2-yl]amino]benzonitrile; 4-[[4-amino-6-(4-nitro-2,6-dimethylphenoxy)-1,3,5-triazin-2-yl] Amino]benzonitrile; 4-[[4-amino-6-(2,6-dibromo-4-methylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-Amino-6-(4-formyl-2,6-dimethylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[ 4-amino-6-[(2,4-dichlorophenyl)thio]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-[(5-acetyl Base-2,3-dihydro-7-methyl-1H-inden-4-yl)oxy]-6-amino-1,3,5-triazin-2-yl]amino]benzonitrile; 4- [[4-amino-6-[(4-bromo-2-chloro-6-methylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[ 4-amino-6-[(2-chloro-4,6-dimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-amino -6-[[2,4-Dichloro-6-(trifluoromethyl)phenyl]amino]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4- Amino-6-[methyl(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-amino-6 -[[2,6-dibromo-4-methylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile; 4-[[4-amino-6-[[ 2,6-dibromo-4-(1-methylethyl)phenyl]amino]-1,3,5-triazin-2-yl]amino]benzonitrile; their N-oxides, pharmaceutical Acceptable addition salts or stereochemical isomeric forms. 14. A compound as claimed in any one of claims 6 to 13 for use as a medicament. 15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as claimed in claims 6 to 13. 16. Process for the preparation of a pharmaceutical composition as claimed in claim 15, characterized in that a therapeutically effective amount of a compound as claimed in claims 6 to 13 is intimately mixed with a pharmaceutically acceptable carrier. 17. Process for the preparation of compounds as claimed in claim 6, characterized in that: a) reacting the intermediate of formula (II) with the amino derivative of formula (III) in a reaction inert solvent and optionally in the presence of a suitable base;

wherein W ¹ is a suitable leaving group and R ¹ , R ² , R ³ , R ^4' , L and A' are as defined in claim 6; b) splitting the intermediate of formula (IV-c) by using a suitable splitting agent

wherein R ³ , R ^4' , L and A' are as defined in claim 6 and - are part of a Rink amide resin, whereby a compound of formula (I'-a) is obtained; or if desired, as known in the art Transformation methods by converting compounds of formula (I') into each other, and additionally, if desired, converting compounds of formula (I') into therapeutically active non-toxic acid addition salts by treatment with an acid, or converting the compounds of formula (I') by treatment with a base ') compound into a therapeutically active non-toxic base addition salt, or conversely, by treatment with a base to convert the acid addition salt form into the free base, or by treating the base addition salt with an acid Conversion to the free acids; and, if desired, preparation of their stereochemically isomeric forms or N-oxides. 18. Combination of a compound of formula (I) as defined in claim 1 with another antiretroviral compound. 19. Combination of a compound of formula (I') as defined in claim 6 with another antiretroviral compound. 20. A combination as claimed in claim 18 or 19 for use as a medicament. twenty one. Products containing (a) a compound of formula (I) as defined in claim 1 and (b) another antiretroviral compound as combined preparations for simultaneous, separate or sequential use in anti-HIV therapy. twenty two. A product containing (a) a compound of formula (I') as defined in claim 6 and (b) another antiretroviral compound as a combined preparation for simultaneous, separate or sequential use in anti-HIV therapy. twenty three. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound of formula (I) as defined in claim 1 and (b) another antiretroviral compound. twenty four. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredients (a) a compound of formula (I') as defined in claim 6 and (b) another antiretroviral compound. 25． Compound of formula (II) wherein R4 ^' is as defined in claim 6, ^R3 is hydrogen, A' is CH, ^W1 is halogen, and L is as defined in claim 1, with the proviso that ^R5 is not p-cyano-phenyl, p-nitro-phenyl, p-methoxy-phenyl and p-aminocarbonyl-phenyl, and R ⁶ is not 2-(4-hydroxyphenyl)ethyl]amino.